Neurological symptoms with methamphetamine (METH) toxicity of the nigrostriatal system, both in rodent models and in drug abusers, are associated with neuroinflammation, a fundamental reaction to brain injury characterized by activated microglia and astrocytes, local expression of inflammatory mediators, and possible infiltration of peripheral cells such as monocytes. This prominent and local tissue response most likely represents an adaptive and restorative repair process. Yet reminiscent of many inflammatory conditions in peripheral diseases, neuroinflammation can also contribute to the pathophysiology of CNS disorders. Thus observations of neuroinflammation in the setting of METH neurotoxicity raise questions about the contribution of glial directed inflammation to neuronal damage as well as the possible mechanisms underlying this association. One such mechanism is oxidative stress, which is known to occur in both METH toxicity and neuroinflammation. Among HIV infected individuals, METH abuse is associated with significant enhancement of HIV encephalitis, greater neuropathology, and increased expression of inflammation-associated genes. Thus neuroinflammation represents a factor common to both METH exposure and CNS HIV infection that may underlie the enhanced disease and neuropathology seen when these two risk factors coexist. One of the major driving forces in CNS inflammation is the proinflammatory cytokine interleukin (IL)-1[unreadable], which is produced by activated microglia. Among its many actions, IL-1[unreadable] promotes phenotypic activation of astrocytes leading to expression of other inflammatory mediators including chemokines, which facilitate CNS infiltration by monocytes and other blood-borne cells. Moreover, there is clear evidence that IL-1 is an important contributor to neuronal damage in several CNS injury and disease models. We have recently developed a transgenic mouse model that provides temporal and spatial control of sustained IL-1[unreadable] expression. We propose using this mouse to test the hypothesis that coexistent neuroinflammation enhances METH-induced damage in the ventral midbrain dopaminergic system. A corollary hypothesis is that attenuation of neuroinflammation will protect against METH neurotoxicity. Finally, we hypothesize that one mechanism underlying the association between neuroinflammation and METH toxicity is production of microglial/ macrophage derived reactive oxygen species (ROS). To explore these hypotheses, we will: 1) quantify striatal dopaminergic nerve terminal toxicity elicited by METH exposure in the presence of sustained neuroinflammation;2) determine whether abrogation of IL-1 signaling reduces neurotoxicity following METH exposure, and 3) characterize oxidant injury in METH and METH + neuroinflammation elicited neurotoxicity. By better understanding the role of neuroinflammation in METH-associated neurotoxicity, we may be able to develop strategies to curb the neurological side effects of METH abuse, particularly when associated with conditions like HIV where neuroinflammation is prominent.